Chronic Hypertension and Pregnancy (CHAP) Project (CHAP)

A Pragmatic Multicenter Randomized Clinical Trial (RCT) of Antihypertensive Therapy for Mild Chronic Hypertension During Pregnancy: Chronic Hypertension and Pregnancy (CHAP) Project

The purpose of this study is to evaluate whether a blood pressure treatment strategy during pregnancy to achieve targets that are recommended for non-pregnant reproductive-age adults (<140/90 mmHg) compared ACOG- recommended standard during pregnancy (no treatment unless BP is severe) is effective and safe.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Anti-hypertensive therapy; Other: No anti-hypertensive therapy (unless BP is severe)

Detailed Description

During pregnancy, chronic hypertension (CHTN) is the most common major medical disorder encountered, occurring in 2-6%. The substantial negative effect of CHTN on pregnancy includes a consistent 3- to 5-fold increase in superimposed preeclampsia and adverse perinatal outcomes (fetal or neonatal death, preterm birth -PTB, poor fetal growth and placental abruption) and possibly a 5- to10-fold increase in maternal cardiovascular and other complications (death, cerebrovascular accident, pulmonary edema and acute renal failure). Mild CHTN (BP <160/110) contributes to a large proportion of these adverse outcomes. While antihypertensive treatment of CHTN is standard for the general population, it is uncertain whether treatment during pregnancy reduces maternal or fetal complications, and there are concerns that decreased arterial pressure may reduce fetal blood flow and cause poor fetal growth or small-for-gestational-age (SGA) infants. Some authorities, including the American College of Obstetricians and Gynecologists (ACOG) and American Society of Hypertension (ASH) recommend withholding antihypertensive therapy for mild CHTN, particularly if BP is <160/105-110 mmHg. The recommendation to withhold antihypertensive treatment in pregnancy conflicts with the broader public health goal to reduce BP in those with CHTN and there is no evidence that discontinuing therapy during the brief period of pregnancy affects maternal outcomes (other than reducing the severe hypertension). For over a decade, authorities have consistently called for well-designed and powered trials to delineate the benefits and risks of pharmacologic therapy for CHTN during pregnancy.

Therefore, our multicenter consortium proposes the Chronic Hypertension and Pregnancy (CHAP) Project, a large pragmatic randomized trial with a primary aim to evaluate the benefits and harms of pharmacologic treatment of mild CHTN in pregnancy.

• Study Type: Interventional
• Enrollment (Actual): 2408
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham, Clinical Coordinating Center
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham, Data Coordinating Center
    • Mobile, Alabama, United States, 36604
      • University of South Alabama
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Colton, California, United States, 92324
      • Arrowhead Regional Medical Center
    • San Diego, California, United States, 92110
      • University of California, San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94110
      • General Hospital of San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Boulder, Colorado, United States, 80204
      • University of Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Northwestern
  • Indiana
    • Bloomington, Indiana, United States, 47405
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Lawrence, Kansas, United States, 66045
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane
    • New Orleans, Louisiana, United States, 70115
      • Ochsner Health System/Medical Center
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical College
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson Medical School
    • New Brunswick, New Jersey, United States, 08901
      • St. Peters University Hospital
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School
    • Sewell, New Jersey, United States, 08080
      • Virtua Medical Group
  • New York
    • Flushing, New York, United States, 11355
      • New York Presbyterian Queens
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • Weill Cornell
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
    • Durham, North Carolina, United States, 27704
      • Duke Regional Medical Center
    • Raleigh, North Carolina, United States, 27610
      • WakeMed
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • TriHealth, Inc
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Fairview
    • Cleveland, Ohio, United States, 44109
      • Case Western/Metro Health
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Mayfield Heights, Ohio, United States, 44124
      • Cleveland Clinic-Hillcrest Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18101
      • Lehigh Valley Hospital/Health Network
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's University Health Network
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Clinic
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Philadelphia, Pennsylvania, United States, 19104
      • Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19019
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15201
      • University of Pittsburg/Magee Women's Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02912
      • Brown (WIHRI)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee Health Science Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Galveston, Texas, United States, 77555
      • UT Medical Branch
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • UT Houston
  • Utah
    • Ogden, Utah, United States, 84403
      • Mckay Dee Hospital
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
    • Salt Lake City, Utah, United States, 84132
      • Intermountain Healthcare
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Health System
    • Madison, Wisconsin, United States, 53715
      • Unity Point Health-Meriter Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53233
      • Aurora Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Women with chronic hypertension in pregnancy with new or untreated chronic hypertension, blood pressure 140-159 systolic or 90-104 diastolic OR known chronic hypertension on monotherapy and taking any antihypertensive and blood pressure ≤159/104 (including those with blood pressure <140/90);
2. Singleton; and
3. viable pregnancy <23 weeks of gestation.

Exclusion Criteria:

1. Blood pressures prior to randomization ≥160 systolic or ≥105 diastolic (with or without treatment);
2. Severe hypertension including patients currently treated with >1 antihypertensive medication (more likely to have severe chronic hypertension);
3. Multi-fetal pregnancy;
4. Known secondary cause of chronic hypertension;

5. High-risk co-morbidities for which treatment may be indicated:

   • Diabetes mellitus diagnosed at age ≤10 years or duration of diagnosis ≥20 years
   • Diabetes mellitus complicated by end organ damage (retinopathy, nephropathy, heart disease, transplant)

   • Chronic kidney disease - including baseline proteinuria (>300mg/24-hr, protein/creatinine ratio ≥0.3, or persistent 1+ proteinuria*) or creatinine >1.2.

     *If a dipstick value at screening is more than trace, a clean catch or catheter urine should be obtained and re-tested by dipstick. If this shows trace or absence of protein, the patient is included. If it again shows 1+ protein, the patient is excluded until a 24-hr urine <300mg/24hr or p/c ratio is <0.3. If a p/c ratio is >0.3, the patient may be included if a 24-hour urine is < 300 mg.

   • Cardiac disorders: cardiomyopathy, angina, CAD
   • Prior stroke
   • Retinopathy
   • Sickle cell disease
6. Known major fetal anomaly;
7. Known fetal demise;
8. Suspected IUGR;
9. Membrane rupture or planned termination prior to randomization;
10. Plan to deliver outside the consortium centers (unless approved by the Clinical Coordinating Center) or unlikely to follow-up in the opinion of study staff or previous participation in this trial;
11. Contraindication to labetalol and nifedipine (e.g. know hypersensitivity);
12. Current substance abuse or addiction (cocaine, methamphetamine)
13. Participation in another trial without prior approval (CHAP participants will not be enrolled in other trials without prior approval by protocol committee)
14. Physician or provider refusal
15. Patient refusal *The minimum age varies by center

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anti-hypertensive therapy to goal <140/90 mmHg; Labetalol or Nifedipine ER will be used as first-line to achieve goal; if necessary Nifedipine ER or Labetalol will be second-line antihypertensive. Rarely, other antihypertensive medications may also be used	Drug: Anti-hypertensive therapy; 1st line anti-hypertensive (Labetalol or Nifedipine ER) started; escalate to maximum dose and a preferred 2nd line medication if needed (nifedipine ER or Labetalol); Other Names: Adalat; Trandate; Procardia XL; Normodyne
Active Comparator: No anti-hypertensive unless BP is severe (≥160/105 mmHg; Antihypertensive therapy given only if BP becomes severe (defined as BP ≥160/105). The lowest dose of anti-hypertensive needed to keep blood pressure below this threshold will be given (1st-line - Labetalol or Nifedipine ER and 2nd-line - Labetalol or Nifedipine ER). Rarely other medications may be used	Other: No anti-hypertensive therapy (unless BP is severe); Treatment will not be started if blood pressure remains <160/105; for blood pressure ≥160/105, treatment with labetalol or Nifedipine ER will be initiated and maintained at lowest dose needed to keep blood pressure under 160/105.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Adverse Perinatal Outcome	One or more severe outcomes including fetal death or neonatal death up to discharge or 90 days if prior; preeclampsia with severe features up to 2 weeks postpartum (Severe hypertension and proteinuria or hypertension and severe features per ACOG); placental abruption; or indicated PTB <35 weeks (not due to spontaneous preterm labor or membrane rupture).	Up to 2 weeks postpartum for preeclampsia or 90 days for neonatal death
Small for Gestational Age (Safety)	Birth weight less than 10th percentile for gestational age at birth according to accepted national standard	Until delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Maternal Death or Severe Cardiovascular Morbidity	One or more of maternal death, new heart failure, stroke, encephalopathy, angina, myocardial infarction or ischemia, pulmonary edema, ICU admission/intubation, or renal failure	Up to 6 weeks (4-12 weeks) after delivery
Severe Maternal Hypertension + Components of the Primary Composite Endpoint	Persistent severe hypertension with or without proteinuria + the primary composite	Up to 2 weeks postpartum or 90 days for neonatal death
Preterm Birth and Indicated Preterm Birth (<37 Weeks)	Preterm birth and Indicated preterm birth (<37 weeks) includes any preterm birth less than 37 weeks	Until delivery
Composite of Severe Neonatal Morbidities	One or more of Bronchopulmonary dysplasia (BPD), Retinopathy of prematurity (ROP), Necrotizing enterocolitis (NEC), Intraventricular hemorrhage (VH) grade III/IV	Up to 90 days post delivery
Adherence to Treatment After Delivery	Counts with high adherence to antihypertensive therapy after delivery for those prescribed medications.	6 weeks (4-12 weeks) after delivery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypoglycemia	Prevalence of hypoglycemia	From delivery to hospital discharge (2 - 3 days after delivery)
Bradycardia	Prevalence of bradycardia	From delivery to hospital discharge (2 - 3 days after delivery)
Hypotension	Incidence (%) with hypotension	From delivery to hospital discharge (2 - 3 days after delivery)
Hyperbilirubinemia	Incidence (%) with hyperbilirubinemia	From delivery to hospital discharge (2 - 3 days after delivery)
Hospitalizations	Number of hospitalizations before or after delivery	Up to 3 months postpartum
Superimposed Preeclampsia	Mild or severe, including eclampsia	Up to 2 weeks after delivery
Superimposed Gestational Hypertension	Persistent worsening hypertension above baseline without pree or proteinuria occurring after 20 weeks gestation	Enrollment (between 6 and 18 weeks gestation) to delivery
Severe Hypertension	Blood pressure ≥160/110	Up to 6 weeks (4-12 weeks) after delivery
Cesarean Delivery	Cesarean delivery	Until delivery
Blood Transfusion	During pregnancy or postpartum	Up to 6 weeks
NICU Admission	Any NICU admission	Up to 6 weeks (4-12 weeks) after delivery
Low Birth Weight	Birth weight <2500g	At birth
Ponderal Index	Mean ponderal index, mass/height^3 at birth	At birth
Head Circumference	Mean head circumference	At birth
Placental Weight	Mean placental weight	At delivery
Respiratory Distress Syndrome (RDS)	Incidence (%) with respiratory distress syndrome (RDS)	From delivery to hospital discharge (2 - 3 days after delivery)
Bronchopulmonary Dysplasia (BPD)	Incidence (%) with bronchopulmonary dysplasia (BPD)	Up to 3 months after delivery
Intubation/Ventilation	Incidence (%) with resuscitation including oxygen, intubation, chest compression/CPR, or CPAP	From delivery to hospital discharge (2 - 3 days after delivery)
Intraventricular Hemorrhage (IVH)	Incidence (%) with any IVH and with IVH Grades III and IV	From delivery to hospital discharge (2 - 3 days after delivery)
Necrotizing Enterocolitis (NEC)	Incidence (%) with necrotizing enterocolitis (NEC)	Up to 3 months after delivery
5-min Apgar Score	Incidence (%) with Apgar score <7 (range 0-10 with lower scores indicating worse outcome)	At delivery
Sepsis	Incidence (%) with proven sepsis	From delivery to hospital discharge (2 - 3 days after delivery)
Unscheduled Prenatal Clinic or ER Visits	Number of unscheduled clinic or ER visits before and after delivery	Up to 3 months after delivery
Postpartum Unscheduled or ER Visits	Number of postpartum unscheduled or ER visits	Up to 3 months after delivery
Postpartum Hospitalizations	Number of postpartum hospitalizations	Up to 3 months after delivery
Neonatal Hospital Stay of 3 or More Days	Frequency of neonatal hospital stays lasting at least 3 days	after delivery

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Medical University of South Carolina; Johns Hopkins University; University of Colorado, Denver; The University of Texas Health Science Center, Houston; Baylor College of Medicine; University of Pennsylvania; Washington University School of Medicine; University of California, San Diego; National Heart, Lung, and Blood Institute (NHLBI); Yale University; Columbia University; University of Pittsburgh; University of Iowa; University of Oklahoma; Emory University; Duke University; Medical College of Wisconsin; Weill Medical College of Cornell University; Oregon Health and Science University; Tulane University; University of California, San Francisco; Vanderbilt University; Stanford University; Ohio State University; University of Kansas Medical Center; Christiana Care Health Services; University of North Carolina, Chapel Hill; University of Texas Southwestern Medical Center; TriHealth Inc.; Temple University; University of Utah; The University of Texas Medical Branch, Galveston; Indiana University; University of Arkansas; University of Tennessee; Denver Health and Hospital Authority; Aurora Health Care; Geisinger Clinic; University of South Alabama; Rutgers, The State University of New Jersey; Winthrop University Hospital; Intermountain Health Care, Inc.; Ochsner Health System; Drexel University College of Medicine; St. Luke's Hospital and Health Network, Pennsylvania; Beaumont Hospital; Lehigh Valley Hospital; San Francisco General Hospital; WakeMed Health and Hospitals; Saint Peters University Hospital; Virtua Medical Group; Latter Day Saints Hospital; Arrowhead Regional Medical Center; New Jersey Medical School; Duke Regional Hospital; McKay-Dee Hospital; New York Hospital Queens; Lyndon B Johnson General Hospital; Bayview Medical Center; Utah Valley Regional Medical Center; Northwestern; Brown (WIHRI); Case Western/Metro Health; Unity Point Health-Meriter Hospital WI; Gundersen Health System; Cleveland Clinic Fairview Hospital; Cleveland Clinic Hillcrest Hospital; Premier Health Miami Valley Hospital
• Investigators: Principal Investigator: Alan Tita, MD, PhD, University of Alabama at Birmingham - Clinical Coordinating Center; Principal Investigator: Gary Cutter, PhD, University of Alabama at Birmingham-Data Coordinating Center; Principal Investigator: Jeff Szychowski, PhD, University of Alabama at Birmingham-Data Coordinating Center

Publications and helpful links

General Publications

• Tita AT, Szychowski JM, Boggess K, Dugoff L, Sibai B, Lawrence K, Hughes BL, Bell J, Aagaard K, Edwards RK, Gibson K, Haas DM, Plante L, Metz T, Casey B, Esplin S, Longo S, Hoffman M, Saade GR, Hoppe KK, Foroutan J, Tuuli M, Owens MY, Simhan HN, Frey H, Rosen T, Palatnik A, Baker S, August P, Reddy UM, Kinzler W, Su E, Krishna I, Nguyen N, Norton ME, Skupski D, El-Sayed YY, Ogunyemi D, Galis ZS, Harper L, Ambalavanan N, Geller NL, Oparil S, Cutter GR, Andrews WW; Chronic Hypertension and Pregnancy (CHAP) Trial Consortium. Treatment for Mild Chronic Hypertension during Pregnancy. N Engl J Med. 2022 May 12;386(19):1781-1792. doi: 10.1056/NEJMoa2201295. Epub 2022 Apr 2.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): April 1, 2022
• Study Completion (Actual): December 16, 2022

Study Registration Dates

• First Submitted: October 28, 2014
• First Submitted That Met QC Criteria: November 19, 2014
• First Posted (Estimate): November 24, 2014

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Pregnancy; Chronic hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Tocolytic Agents; Antihypertensive Agents; Nifedipine
• Other Study ID Numbers: 1U01HL119242-01 (U.S. NIH Grant/Contract); U01HL119242-01 (U.S. NIH Grant/Contract)